Project Summary Geroscience refers to the multi-disciplinary approach to understand, at the molecular level, the relationship be- tween aging-associated pathologies and aging. Unfortunately, there continues to be a fundamental knowledge gap in implicating how these mechanisms predispose to a myriad of diseases with advancing age, including neurodegenerative diseases (ND) like Alzheimer?s disease (AD). This lack of comprehension represents a sig- nificant problem because, until it is recognized, development of interventions that prevent or attenuate this de- bilitating disease will continue to be unattainable. Senescent cells (SnCs) accumulate with age and at sites of age-related pathology and have been demonstrated to actively drive tissue deterioration. As removal of these cells has largely beneficial consequences for aging and lifespan, these cells are particularly attractive candi- dates to test the geroscience hypothesis that attenuated ?rates of aging? may delay neurodegenerative diseas- es and other age-related conditions. The long-term goal of the laboratory is to exploit SnC clearance as a ther- apeutic strategy for a variety of age-related diseases, including AD. Cells with features reminiscent of senes- cence have been observed in post mortem AD patients, therefore the overall objective in this application is to determine whether SnC elimination from established ND models attenuates disease severity. The central hy- pothesis is that SnCs actively drive disease processes and that removal of these cells will prevent or delay AD progression and severity. This hypothesis has been formulated on the basis of unpublished preliminary data produced in the applicants? laboratory included in this application. The rationale for the proposed research is that once it is known how senescence of specific cell types in the brains impacts pathology, it can be tested if novel pharmacological modulations of SnCs and/or their effects influences the disease process. Guided by strong preliminary data, the hypothesis will be tested by pursuing two specific aims: 1) Establish the therapeu- tic potential of SnC removal in ND; and 2) Evaluate how attenuated SnC accumulation impacts ND and normal cognitive aging. Under the first aim, various methods of SnC elimination will be used in established disease to attenuate severity using novel mouse models established as feasible in the applicants? laboratory. Under the second aim, senescence in specific cell types will be prevented to determine how this influences disease se- verity and SnCs will be genetically removed from geriatric mice to determine if this impacts cognition. The ap- proach is innovative, in the applicant?s opinion, because it departs from the status quo by utilizing an entirely novel approach to counteract ND through modulation of SnCs. The proposed research is significant, because it will address key fundamental questions about SnCs in ND and test whether targeting SnCs is a potential ther- apeutic strategy for this disease. This knowledge will pave the way towards transformative clinical interventions for treating or preventing not only ND, but also a broad spectrum of human age-related diseases.